Alzheimer Disease is a malady of unknown etiology, but neuropathological examination of brain tissues of affected individuals reveals characteristic structures known as neuritic (senile) plaques and neurofibrillary tangles. The working hypothesis that guides proposal of the experiments outlined here is that a clear understanding of the biochemical abnormalities that foster the formation of these structures will lead us closer to an understanding of the molecular basis of Alzheimer Disease. Therefore, a series of studies is proposed. Work on the molecular biology of the amyloid precursor protein (APP) will address the cellular consequences of under- and over-production of APP by cultured cells, including microglia. Processing of APP, including possible generation and extrusion of beta- protein, will be studied. The distribution of APP and putative truncated forms will be examined by immunohistochemistry. The cytotoxicity of beta- protein in the brain may comprise membrane function. Antibodies to various parts of the APP will be used to search for Alzheimer specific epitopes in CSF of affected individuals. The paired helical filaments will be examined, and it is anticipated that an understanding of the constituents of PHF will give insights into the mechanisms that lead to their assembly into these pathological structures. Proteases are fundamental to any discussion of tangles and plaques, because if their protein constituents were digested in situ the structures presumably would not form. Thus, work on a recently discovered brain protease, called high molecular weight protease, is included in this proposal. Besides amyloid and tangles, other biochemical aberrations in glucose metabolism, which will be studied in the Program. It is anticipated that integration of the results from these diverse approaches will enhance our understanding of the molecular pathological origins of Alzheimer Disease, and will thus contribute to development of rational therapy for its victims.